Molecular Characterization of Circulating Tumor DNA in Pediatric Rhabdomyosarcoma: A Feasibility Study.
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Authors
Ruhen, O
Lak, NSM
Stutterheim, J
Danielli, SG
Chicard, M
Iddir, Y
Saint-Charles, A
Di Paolo, V
Tombolan, L
Gatz, SA
Aladowicz, E
Proszek, P
Jamal, S
Stankunaite, R
Hughes, D
Carter, P
Izquierdo, E
Wasti, A
Chisholm, JC
George, SL
Pace, E
Chesler, L
Aerts, I
Pierron, G
Zaidi, S
Delattre, O
Surdez, D
Kelsey, A
Hubank, M
Bonvini, P
Bisogno, G
Di Giannatale, A
Schleiermacher, G
Schäfer, BW
Tytgat, GAM
Shipley, J
Lak, NSM
Stutterheim, J
Danielli, SG
Chicard, M
Iddir, Y
Saint-Charles, A
Di Paolo, V
Tombolan, L
Gatz, SA
Aladowicz, E
Proszek, P
Jamal, S
Stankunaite, R
Hughes, D
Carter, P
Izquierdo, E
Wasti, A
Chisholm, JC
George, SL
Pace, E
Chesler, L
Aerts, I
Pierron, G
Zaidi, S
Delattre, O
Surdez, D
Kelsey, A
Hubank, M
Bonvini, P
Bisogno, G
Di Giannatale, A
Schleiermacher, G
Schäfer, BW
Tytgat, GAM
Shipley, J
Document Type
Journal Article
Date
2022-10-01
Date Accepted
2022-08-26
Abstract
PURPOSE: Rhabdomyosarcomas (RMS) are rare neoplasms affecting children and young adults. Efforts to improve patient survival have been undermined by a lack of suitable disease markers. Plasma circulating tumor DNA (ctDNA) has shown promise as a potential minimally invasive biomarker and monitoring tool in other cancers; however, it remains underexplored in RMS. We aimed to determine the feasibility of identifying and quantifying ctDNA in plasma as a marker of disease burden and/or treatment response using blood samples from RMS mouse models and patients. METHODS: We established mouse models of RMS and applied quantitative polymerase chain reaction (PCR) and droplet digital PCR (ddPCR) to detect ctDNA within the mouse plasma. Potential driver mutations, copy-number alterations, and DNA breakpoints associated with PAX3/7-FOXO1 gene fusions were identified in the RMS samples collected at diagnosis. Patient-matched plasma samples collected from 28 patients with RMS before, during, and after treatment were analyzed for the presence of ctDNA via ddPCR, panel sequencing, and/or whole-exome sequencing. RESULTS: Human tumor-derived DNA was detectable in plasma samples from mouse models of RMS and correlated with tumor burden. In patients, ctDNA was detected in 14/18 pretreatment plasma samples with ddPCR and 7/7 cases assessed by sequencing. Levels of ctDNA at diagnosis were significantly higher in patients with unfavorable tumor sites, positive nodal status, and metastasis. In patients with serial plasma samples (n = 18), fluctuations in ctDNA levels corresponded to treatment response. CONCLUSION: Comprehensive ctDNA analysis combining high sensitivity and throughput can identify key molecular drivers in RMS models and patients, suggesting potential as a minimally invasive biomarker. Preclinical assessment of treatments using mouse models and further patient testing through prospective clinical trials are now warranted.
Citation
JCO Precision Oncology, 2022, 6 (6), pp. e2100534 -
Source Title
JCO Precision Oncology
Publisher
LIPPINCOTT WILLIAMS & WILKINS
ISSN
2473-4284
eISSN
2473-4284
2473-4284
2473-4284
Collections
Research Team
Paediatric Tumour Biology
Sarcoma Mol Pathol
Sarcoma Mol Pathol